Dual inhibitors of vista and pd-1 pathways

Abstract

The present disclosure relates to 3-substituted 1,2,4-oxadiazole compounds and their derivatives, which are useful as V-domain immunoglobulin suppressor of T-cell activation (VISTA) inhibitors or as dual inhibitors of VISTA and the programmed cell death 1 (PD-1) signaling pathway. The disclosure also relates to treatment of disorders by inhibiting an immunosuppressive signal induced by VISTA and its ligands, PD-1, PD-L1, and/or PD-L2.

1 - 56 . (canceled) 
     
     
         57 . A method of treating cancer in a subject in need thereof, wherein the cancer is characterized by aberrant V-domain immunoglobulin suppressor of T-cell activation (VISTA) activity, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         G represents hydrogen or (C 1 -C 6 )alkyl; 
         R a  represents (C 1 -C 6 )alkyl substituted with —OH, —C(O)NR x R y , —NR x R y , guanidino, carboxylic acid, heteroaryl, or aryl-OH; 
         R a′  represents hydrogen; or R a  and R a′  taken together with the atom to which they are attached form a 5- to 6-membered ring; 
         R b  represents (C 1 -C 6 )alkyl, optionally substituted with —OH, —C(O)NR x R y , —NR x R y , carboxylic acid, or heteroaryl; wherein the heteroaryl is optionally further substituted with hydroxyl; 
         R c  represents hydrogen; or R b  and R c  taken together with the atoms to which they are attached form a 5- to 6-membered ring; 
         R d  represents H, (C 1 -C 6 )alkyl substituted with —OH, —NR x R y , or carboxylic acid; 
         R e  represents hydrogen; or R d  and R e  taken together with the atoms to which they are attached form a 5- to 6-membered ring optionally containing 1 to 3 heteroatoms selected from O, NH or S; and 
         R x  and R y  independently represent hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )acyl, or (C 1 -C 6 )cycloalkyl; or R x  and R y  taken together with the atom to which they are attached form a 5- to 6-membered ring. 
       
     
     
         58 . The method of  claim 57 , wherein G represents hydrogen or methyl. 
     
     
         59 . The method of  claim 57 , wherein G represents hydrogen. 
     
     
         60 . The method of  claim 57 , wherein Ra represents —(CH 2 ) 2 C(O)OH or (C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl is substituted with —OH, —C(O)NR x R y , —NR x R y , guanidino, heteroaryl, or aryl-OH. 
     
     
         61 . The method of  claim 57 , wherein Ra represents (C 1 -C 4 )alkyl substituted with —OH, —NH 2 , —NH—C(═NH)—NH 2 , carboxylic acid, imidazolyl, or p-OH (phenyl); and R a′  is hydrogen. 
     
     
         62 . The method of  claim 57 , wherein R a  represents —CH 2 OH, —CH(CH 3 )OH, —CH 2 -(p-OH (phenyl)), —(CH 2 ) 4 —NH 2 , —(CH 2 ) 2 C(O)OH, —(CH 2 ) 2 C(O)NH 2 , —CH 2 (imidazolyl), or —(CH 2 ) 3 —NH—C(═NH)—NH 2 . 
     
     
         63 . The method of  claim 57 , wherein R a  represents —CH 2 OH or —CH(CH 3 )OH. 
     
     
         64 . The method of  claim 57 , wherein R a  represents —CH 2 OH. 
     
     
         65 . The method of  claim 57 , wherein R a  and R a′  taken together with the atoms to which they are attached form a cyclopentyl or a cyclohexyl ring. 
     
     
         66 . The method of  claim 57 , wherein R b  represents —CH 2 C(O)OH or (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl is optionally substituted with —OH, —C(O)NR x R y , or heteroaryl, wherein the heteroaryl is optionally further substituted with hydroxyl. 
     
     
         67 . The method of  claim 57 , wherein R b  represents (C 1 -C 4 )alkyl, optionally substituted with —OH, —C(O)NH2, carboxylic acid, indolyl, or —C(O)NH—((C 1 -C 6 )alkyl); and R c  represents hydrogen. 
     
     
         68 . The method of  claim 57 , wherein R b  represents isopropyl, sec-butyl, —CH 2 OH, —CH 2 C(O)NH 2 , —(CH 2 ) 2 C(O)NH 2 , —(CH 2 ) 4 —NH(COCH 3 ), —CH 2 C(O)OH, —(CH 2 ) 2 C(O)OH, —CH 2 (indolyl), —CH 2 C(O)NH(hexyl), or —(CH 2 ) 2 C(O)NH(hexyl). 
     
     
         69 . The method of  claim 57 , wherein R b  represents —CH 2 C(O)NH 2  or —CH 2 C(O)OH. 
     
     
         70 . The method of  claim 57 , wherein R b  represents —CH 2 C(O)NH 2 . 
     
     
         71 . The method of  claim 57 , wherein R b  and R c  taken together with the atoms to which they are attached form a pyrrolidine ring. 
     
     
         72 . The method of  claim 57 , wherein R d  represents (C 1 -C 4 )alkyl substituted with —OH, —NH 2 , or —C(O)OH; and R e  represents hydrogen. 
     
     
         73 . The method of  claim 57 , wherein R d  represents —CH 2 OH, —CH(CH 3 )OH, —(CH 2 ) 4 —NH 2 , or —CH 2 C(O)OH. 
     
     
         74 . The method of  claim 57 , wherein R d  represents —CH 2 OH or —CH(CH 3 )OH. 
     
     
         75 . The method of  claim 57 , wherein R d  represents —CH(CH 3 )OH. 
     
     
         76 . The method of  claim 57 , wherein R d  and R e  taken together with the atoms to which they are attached form a pyrrolidine ring. 
     
     
         77 . The method of  claim 57 , wherein:
 G represents hydrogen or (C 1 -C 6 )alkyl;   R a  represents —(CH 2 ) 2 C(O)OH or (C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl is substituted with-OH, —NR x R y , guanidino, heteroaryl, or aryl-OH;   R a′  represents hydrogen; or R a  and R a′  taken together with the atom to which they are attached form a 5- to 6-membered ring;   R b  represents —CH 2 C(O)OH or —(C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl is optionally substituted with —OH, —C(O)NR x R y , or heteroaryl; wherein the heteroaryl is optionally further substituted with hydroxyl;   R c  represents hydrogen; or R b  and R c  taken together with the atoms to which they are attached form a 5- to 6-membered ring;   R d  represents H, or —(C 1 -C 6 )alkyl substituted with —OH, —NR x R y , or carboxylic acid;   R e  represents hydrogen; or R d  and R e  taken together with the atoms to which they are attached form a 5- to 6-membered ring optionally containing 1 to 3 heteroatoms selected from O, NH or S; and   R x  and R y  independently represent hydrogen, (C 1 -C 6 )alkyl, or (C 2 -C 6 )acyl.   
     
     
         78 . The method of  claim 57 , wherein:
 G represents hydrogen or methyl;   R a  represents —CH 2 OH, —CH(CH 3 )OH, —CH 2 -(p-OH(phenyl)), —(CH 2 ) 4 —NH 2 , —(CH 2 ) 2 COOH, —CH 2 (imidazolyl), or —(CH 2 ) 3 —NH—C(═NH)—NH 2 ;   R a′  represents hydrogen; or R a  and R a′  taken together with the atoms to which they are attached form a cyclopentyl or a cyclohexyl ring;   R b  represents isopropyl, sec-butyl, —CH 2 OH, —CH 2 C(O)NH 2 , —(CH 2 ) 2 C(O)NH 2 , —CH 2 C(O)OH, —(CH 2 ) 4 —NH(COCH 3 ), —CH 2 (indolyl), —CH 2 C(O)NH(hexyl), or —(CH 2 ) 2 C(O)NH(hexyl);   R c  represents hydrogen; or R b  and R c  taken together with the atoms to which they are attached to form a pyrrolidine ring;   R d  represents —CH 2 OH, —CH(CH 3 )OH, —(CH 2 ) 4 —NH 2 , or —(CH 2 ) 2 C(O)OH; and   R e  represents hydrogen; or R d  and R e  taken together with the atoms to which they are attached to form a pyrrolidine ring.   
     
     
         79 . The method  claim 77 , wherein R a  represents —CH 2 OH or —CH(CH 3 OH, R b  represents —CH 2 C(O)NH 2  or —CH 2 C(O)OH, and R d  represents —CH 2 OH or —CH(CH 3 )OH. 
     
     
         80 . The method of  claim 79  wherein R a  represents —CH 2 OH or —CH(CH 3 )OH, R b  represents —CH 2 C(O)NH 2 , and R d  represents —CH(CH 3 )OH. 
     
     
         81 . The method of  claim 79  wherein R a  represents —CH 2 OH, R b  represents —CH 2 C(O)NH 2 , and R d  represents —CH(CH 3 )OH. 
     
     
         82 . The method of  claim 79  wherein R a  represents —CH(CH 3 )OH, R b  represents —CH 2 C(O)NH 2 , and R d  represents —CH 2 OH. 
     
     
         83 . The method of  claim 57 , wherein the compound selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         84 . The method of  claim 57 , wherein the cancer is further characterized by aberrant expression of PD-1, PD-L1, or PD-L2. 
     
     
         85 . The method of  claim 57 , wherein the treatment of cancer comprises inhibiting growth of tumor cells or metastasis. 
     
     
         86 . The method of  claim 57 , wherein the cancer is selected from small cell lung cancer, multiple myeloma, bladder carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic cancer. 
     
     
         87 . The method of  claim 57 , wherein the cancer is selected from blastoma, breast cancer, epithelial cancer, colon cancer, lung cancer, melanoma, prostate cancer, renal cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, cancer of the anal region, cancer of the peritoneum, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical cancer, vaginal cancer, vulval cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma, cancer of the urethra, cancer of the penis, chronic or acute leukemia, solid tumors of childhood, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mesothelioma, thymic carcinoma, myeloma, cancer of the bladder, cancer of the ureter, carcinoma of the renal pelvis, liver cancer, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, salivary gland carcinoma, squamous cell cancer, abnormal vascular proliferation associated with phakomatoses, edema, Meigs' syndrome, Merkel cell carcinoma, and environmentally induced cancers.